Genetic regulation of the RUNX transcription factor family has antitumor effects
Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect m...
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| Veröffentlicht in: | The Journal of clinical investigation 2017-06, Vol.127 (7), p.2815-2828 |
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| creator | Morita, Ken Suzuki, Kensho Maeda, Shintaro Matsuo, Akihiko Mitsuda, Yoshihide Tokushige, Chieko Kashiwazaki, Gengo Taniguchi, Junichi Maeda, Rina Noura, Mina Hirata, Masahiro Kataoka, Tatsuki Yano, Ayaka Yamada, Yoshimi Kiyose, Hiroki Tokumasu, Mayu Matsuo, Hidemasa Tanaka, Sunao Okuno, Yasushi Muto, Manabu Naka, Kazuhito Ito, Kosei Kitamura, Toshio Kaneda, Yasufumi Liu, Paul P Bando, Toshikazu Adachi, Souichi Sugiyama, Hiroshi Kamikubo, Yasuhiko |
| description | Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the antitumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger antitumor effect relative to suppression of individual RUNX members. Switching off the RUNX cluster using alkylating agent-conjugated pyrrole-imidazole (PI) polyamides, which were designed to specifically bind to consensus RUNX-binding sequences, was highly effective against AML cells and against several poor-prognosis solid tumors in a xenograft mouse model of AML without notable adverse events. Taken together, these results identify a crucial role for the RUNX cluster in the maintenance and progression of cancer cells and suggest that modulation of the RUNX cluster using the PI polyamide gene-switch technology is a potential strategy to control malignancies. |
| doi_str_mv | 10.1172/JCI91788 |
| format | Article |
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Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the antitumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger antitumor effect relative to suppression of individual RUNX members. Switching off the RUNX cluster using alkylating agent-conjugated pyrrole-imidazole (PI) polyamides, which were designed to specifically bind to consensus RUNX-binding sequences, was highly effective against AML cells and against several poor-prognosis solid tumors in a xenograft mouse model of AML without notable adverse events. Taken together, these results identify a crucial role for the RUNX cluster in the maintenance and progression of cancer cells and suggest that modulation of the RUNX cluster using the PI polyamide gene-switch technology is a potential strategy to control malignancies.</description><identifier>ISSN: 0021-9738</identifier><identifier>EISSN: 1558-8238</identifier><identifier>DOI: 10.1172/JCI91788</identifier><identifier>PMID: 28530640</identifier><language>eng</language><publisher>United States: American Society for Clinical Investigation</publisher><subject>Acute myeloid leukemia ; Animals ; Antineoplastic Agents, Alkylating - chemistry ; Antineoplastic Agents, Alkylating - pharmacology ; Antitumor activity ; Apoptosis ; Bioinformatics ; Biomedical research ; Cancer ; Carcinogenesis ; Cbfa-1 protein ; Cell cycle ; Cell death ; Cell Line, Tumor ; Core Binding Factor alpha Subunits - genetics ; Core Binding Factor alpha Subunits - metabolism ; Deoxyribonucleic acid ; DNA ; Gene expression ; Gene regulation ; Genetic aspects ; Genomes ; Genomics ; Health aspects ; Humans ; Imidazole ; Leukemia ; Leukemia, Myeloid, Acute - drug therapy ; Leukemia, Myeloid, Acute - genetics ; Leukemia, Myeloid, Acute - metabolism ; Mice ; Mice, Inbred NOD ; Mutation ; Myeloid leukemia ; Nylons - chemistry ; Nylons - pharmacology ; p53 Protein ; Polyamides ; Prevention ; Pyrroles - chemistry ; Pyrroles - pharmacology ; Runx1 protein ; Runx3 protein ; Solid tumors ; Transcription factors ; Tumor suppressor genes ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism ; Tumors ; Xenograft Model Antitumor Assays ; Xenografts</subject><ispartof>The Journal of clinical investigation, 2017-06, Vol.127 (7), p.2815-2828</ispartof><rights>COPYRIGHT 2017 American Society for Clinical Investigation</rights><rights>Copyright American Society for Clinical Investigation Jul 2017</rights><rights>Copyright © 2017, American Society for Clinical Investigation 2017 American Society for Clinical Investigation</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c497t-632068ba368a30c9c2b5dfc4e5b23ff2bd7b5fef27d7623f24b8683bd72923863</citedby><cites>FETCH-LOGICAL-c497t-632068ba368a30c9c2b5dfc4e5b23ff2bd7b5fef27d7623f24b8683bd72923863</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490777/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490777/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28530640$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Morita, Ken</creatorcontrib><creatorcontrib>Suzuki, Kensho</creatorcontrib><creatorcontrib>Maeda, Shintaro</creatorcontrib><creatorcontrib>Matsuo, Akihiko</creatorcontrib><creatorcontrib>Mitsuda, Yoshihide</creatorcontrib><creatorcontrib>Tokushige, Chieko</creatorcontrib><creatorcontrib>Kashiwazaki, Gengo</creatorcontrib><creatorcontrib>Taniguchi, Junichi</creatorcontrib><creatorcontrib>Maeda, Rina</creatorcontrib><creatorcontrib>Noura, Mina</creatorcontrib><creatorcontrib>Hirata, Masahiro</creatorcontrib><creatorcontrib>Kataoka, Tatsuki</creatorcontrib><creatorcontrib>Yano, Ayaka</creatorcontrib><creatorcontrib>Yamada, Yoshimi</creatorcontrib><creatorcontrib>Kiyose, Hiroki</creatorcontrib><creatorcontrib>Tokumasu, Mayu</creatorcontrib><creatorcontrib>Matsuo, Hidemasa</creatorcontrib><creatorcontrib>Tanaka, Sunao</creatorcontrib><creatorcontrib>Okuno, Yasushi</creatorcontrib><creatorcontrib>Muto, Manabu</creatorcontrib><creatorcontrib>Naka, Kazuhito</creatorcontrib><creatorcontrib>Ito, Kosei</creatorcontrib><creatorcontrib>Kitamura, Toshio</creatorcontrib><creatorcontrib>Kaneda, Yasufumi</creatorcontrib><creatorcontrib>Liu, Paul P</creatorcontrib><creatorcontrib>Bando, Toshikazu</creatorcontrib><creatorcontrib>Adachi, Souichi</creatorcontrib><creatorcontrib>Sugiyama, Hiroshi</creatorcontrib><creatorcontrib>Kamikubo, Yasuhiko</creatorcontrib><title>Genetic regulation of the RUNX transcription factor family has antitumor effects</title><title>The Journal of clinical investigation</title><addtitle>J Clin Invest</addtitle><description>Runt-related transcription factor 1 (RUNX1) is generally considered to function as a tumor suppressor in the development of leukemia, but a growing body of evidence suggests that it has pro-oncogenic properties in acute myeloid leukemia (AML). Here we have demonstrated that the antileukemic effect mediated by RUNX1 depletion is highly dependent on a functional p53-mediated cell death pathway. Increased expression of other RUNX family members, including RUNX2 and RUNX3, compensated for the antitumor effect elicited by RUNX1 silencing, and simultaneous attenuation of all RUNX family members as a cluster led to a much stronger antitumor effect relative to suppression of individual RUNX members. Switching off the RUNX cluster using alkylating agent-conjugated pyrrole-imidazole (PI) polyamides, which were designed to specifically bind to consensus RUNX-binding sequences, was highly effective against AML cells and against several poor-prognosis solid tumors in a xenograft mouse model of AML without notable adverse events. Taken together, these results identify a crucial role for the RUNX cluster in the maintenance and progression of cancer cells and suggest that modulation of the RUNX cluster using the PI polyamide gene-switch technology is a potential strategy to control malignancies.</description><subject>Acute myeloid leukemia</subject><subject>Animals</subject><subject>Antineoplastic Agents, Alkylating - chemistry</subject><subject>Antineoplastic Agents, Alkylating - pharmacology</subject><subject>Antitumor activity</subject><subject>Apoptosis</subject><subject>Bioinformatics</subject><subject>Biomedical research</subject><subject>Cancer</subject><subject>Carcinogenesis</subject><subject>Cbfa-1 protein</subject><subject>Cell cycle</subject><subject>Cell death</subject><subject>Cell Line, Tumor</subject><subject>Core Binding Factor alpha Subunits - genetics</subject><subject>Core Binding Factor alpha Subunits - metabolism</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>Gene expression</subject><subject>Gene regulation</subject><subject>Genetic aspects</subject><subject>Genomes</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>Humans</subject><subject>Imidazole</subject><subject>Leukemia</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>Leukemia, Myeloid, Acute - genetics</subject><subject>Leukemia, Myeloid, Acute - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mutation</subject><subject>Myeloid leukemia</subject><subject>Nylons - chemistry</subject><subject>Nylons - pharmacology</subject><subject>p53 Protein</subject><subject>Polyamides</subject><subject>Prevention</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacology</subject><subject>Runx1 protein</subject><subject>Runx3 protein</subject><subject>Solid tumors</subject><subject>Transcription factors</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>Tumors</subject><subject>Xenograft Model Antitumor Assays</subject><subject>Xenografts</subject><issn>0021-9738</issn><issn>1558-8238</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BEC</sourceid><sourceid>BENPR</sourceid><recordid>eNpdkV1rFDEUhkOp2O0q9BfIQEF6M5rvZG4KZdFaKbaIBe9CJpvspGQm2yQj9N-btR9qrw685-E9Hy8ARwh-QEjgj19XFx0SUu6BBWJMthITuQ8WEGLUdoLIA3CY8y2EiFJGX4MDLBmBnMIFuD63ky3eNMlu5qCLj1MTXVMG23y_-fazKUlP2SS__dNx2pSYahl9uG8GnRs9FV_msYrWOWtKfgNeOR2yfftYl-Dm86cfqy_t5dX5xerssjW0E6XlBEMue0241ASazuCerZ2hlvWYOIf7teiZsw6LteBVwbSXXJIq464ex8kSnD74bud-tGtjp7pqUNvkR53uVdRe_d-Z_KA28ZditINCiGpw8miQ4t1sc1Gjz8aGoCcb56xQBxFBeDd9CY5foLdxTlM9r1KIc4oEYZV6_0BtdLBqsDqUIccw7z6X1Rmr7ydECvZ3skkx52Td89YIql2e6inPir7798pn8ClA8hvP5Jo5</recordid><startdate>20170630</startdate><enddate>20170630</enddate><creator>Morita, Ken</creator><creator>Suzuki, Kensho</creator><creator>Maeda, Shintaro</creator><creator>Matsuo, Akihiko</creator><creator>Mitsuda, Yoshihide</creator><creator>Tokushige, Chieko</creator><creator>Kashiwazaki, Gengo</creator><creator>Taniguchi, Junichi</creator><creator>Maeda, Rina</creator><creator>Noura, Mina</creator><creator>Hirata, Masahiro</creator><creator>Kataoka, Tatsuki</creator><creator>Yano, Ayaka</creator><creator>Yamada, Yoshimi</creator><creator>Kiyose, Hiroki</creator><creator>Tokumasu, Mayu</creator><creator>Matsuo, Hidemasa</creator><creator>Tanaka, Sunao</creator><creator>Okuno, Yasushi</creator><creator>Muto, Manabu</creator><creator>Naka, Kazuhito</creator><creator>Ito, Kosei</creator><creator>Kitamura, Toshio</creator><creator>Kaneda, Yasufumi</creator><creator>Liu, Paul P</creator><creator>Bando, Toshikazu</creator><creator>Adachi, Souichi</creator><creator>Sugiyama, Hiroshi</creator><creator>Kamikubo, Yasuhiko</creator><general>American Society for Clinical Investigation</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7RV</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M7P</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>S0X</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170630</creationdate><title>Genetic regulation of the RUNX transcription factor family has antitumor effects</title><author>Morita, Ken ; Suzuki, Kensho ; Maeda, Shintaro ; Matsuo, Akihiko ; Mitsuda, Yoshihide ; Tokushige, Chieko ; Kashiwazaki, Gengo ; Taniguchi, Junichi ; Maeda, Rina ; Noura, Mina ; Hirata, Masahiro ; Kataoka, Tatsuki ; Yano, Ayaka ; Yamada, Yoshimi ; Kiyose, Hiroki ; Tokumasu, Mayu ; Matsuo, Hidemasa ; Tanaka, Sunao ; Okuno, Yasushi ; Muto, Manabu ; Naka, Kazuhito ; Ito, Kosei ; Kitamura, Toshio ; Kaneda, Yasufumi ; Liu, Paul P ; Bando, Toshikazu ; Adachi, Souichi ; Sugiyama, Hiroshi ; Kamikubo, Yasuhiko</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c497t-632068ba368a30c9c2b5dfc4e5b23ff2bd7b5fef27d7623f24b8683bd72923863</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Acute myeloid leukemia</topic><topic>Animals</topic><topic>Antineoplastic Agents, Alkylating - 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| ispartof | The Journal of clinical investigation, 2017-06, Vol.127 (7), p.2815-2828 |
| issn | 0021-9738 1558-8238 |
| language | eng |
| recordid | cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_5490777 |
| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central; Alma/SFX Local Collection; Journals@Ovid Complete |
| subjects | Acute myeloid leukemia Animals Antineoplastic Agents, Alkylating - chemistry Antineoplastic Agents, Alkylating - pharmacology Antitumor activity Apoptosis Bioinformatics Biomedical research Cancer Carcinogenesis Cbfa-1 protein Cell cycle Cell death Cell Line, Tumor Core Binding Factor alpha Subunits - genetics Core Binding Factor alpha Subunits - metabolism Deoxyribonucleic acid DNA Gene expression Gene regulation Genetic aspects Genomes Genomics Health aspects Humans Imidazole Leukemia Leukemia, Myeloid, Acute - drug therapy Leukemia, Myeloid, Acute - genetics Leukemia, Myeloid, Acute - metabolism Mice Mice, Inbred NOD Mutation Myeloid leukemia Nylons - chemistry Nylons - pharmacology p53 Protein Polyamides Prevention Pyrroles - chemistry Pyrroles - pharmacology Runx1 protein Runx3 protein Solid tumors Transcription factors Tumor suppressor genes Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism Tumors Xenograft Model Antitumor Assays Xenografts |
| title | Genetic regulation of the RUNX transcription factor family has antitumor effects |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-31T08%3A52%3A54IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Genetic%20regulation%20of%20the%20RUNX%20transcription%20factor%20family%20has%20antitumor%20effects&rft.jtitle=The%20Journal%20of%20clinical%20investigation&rft.au=Morita,%20Ken&rft.date=2017-06-30&rft.volume=127&rft.issue=7&rft.spage=2815&rft.epage=2828&rft.pages=2815-2828&rft.issn=0021-9738&rft.eissn=1558-8238&rft_id=info:doi/10.1172/JCI91788&rft_dat=%3Cgale_pubme%3EA500133875%3C/gale_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1916641735&rft_id=info:pmid/28530640&rft_galeid=A500133875&rfr_iscdi=true |